The purpose of this project is to study the pathophysiology of HIV disease in the context of anti-retroviral therapy and to develop novel anti-retroviral treatment strategies. This includes the evaluation of new agents, studies of the efficacy and toxicity of licensed agents and evaluation of the long-term consequences of anti-retroviral therapy. An emphasis is placed on developing long-term strategies for the management of patients with HIV disease. This work is closely coordinated with projects on immunopathogenesis and immune based therapies. HIV infects and destroys the CD4 limb of the immune system. Effective anti-retroviral therapy decreases the rate of viral replication and is associated with increases in CD4 T cell counts. While laboratory analysis of the post-treatment immune system suggests that immune reconstitution is incomplete, the clinical observations suggest marked improvement. As part of this project patients with a history of opportunistic infections, such as CMV, whose CD4 counts have increased in the setting anti-retroviral therapy have their prophylactic regimens stopped to viral burden, lymphocyte turnover, and lymphocyte architecture. The initial enthusiasm for the success of combination anti-retroviral therapy has been tempered with the realization that, for many patients, long-term control of virus has not been possible. This is especially true for the subset of patients who were treated in the earliest days of anti-retroviral therapy. This subset of patients is involved in a series of studies designed to evaluate new anti-retroviral drugs, such as abacavir, amprenavir and efavirenz and to evaluate at the potential value of drug resistance measurements in the selection of anti-retroviral drugs. Studies are also underway to evaluate novel strategies, such as interfering with the zinc finger domain of the viral p7 protein. The final area studied in the context of this project is in the area of long-term side effects associated with anti-retroviral therapy. Over the past year it has become increasingly apparent that long term suppression of HIV replication is associated with considerable toxicity. Prominent among the complications of anti-retroviral therapy are a lipodystrophy syndrome that has been characterized through a combination of physical, radiological and biochemical studies and crystalluria associated with the popular protease inhibitor, indinavir. In addition, widespread use of combination therapy leads to novel drug-drug interactions that are studied in collaboration with colleagues in the Clinical Center Department of Pharmacy.